A knockout of the caspase 2 gene produces increased resistance of the nigrostriatal dopaminergic pathway to MPTP-induced toxicity

This study investigated the effect of a knockout of the caspase 2 gene on the sensitivity of murine nigral dopaminergic neurons to 1-methyl-4-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. Female wild type (WT), heterozygous caspase 2 NL (HET) and homozygous caspase 2 null (NL) mice were treated with cumulative dosages of 0, 10, 15 or 20 mg/kg MPTP free base. Without MPTP treatment, one week later dopamine (DA) levels were not significantly different in HET or NL versus WT mice. Twenty mg/kg MPTP reduced striatal DA in WT and HET (p < 0.01) but not NL mice. This same MPTP dosage regimen also induced a significantly greater decrease in tyrosine hydroxylase immunopositive (TH+) protein in striata of WT compared to NL mice (p < 0.001).Subsequently, WT and NL mice were treated daily with 20 mg/kg MPTP for 3 days and 25 mg/kg MPTP for 2 additional days, and TH+ neurons in the substantia nigra (SN) were estimated using unbiased stereology. When compared to untreated WT, the numbers of TH+ neurons were significantly lower in the SN of untreated NL mice (p < 0.05). Treatment with the MPTP regimen significantly reduced TH+ neurons in WT mice but not NL mice.In primary mesencephalic cultures both the cell bodies and the neuronal processes of TH immunopositive (TH+) neurons from NL embryos were significantly (p < 0.001) more resistant to 10 μM MPP+ compared to WT. Following MPP+ treatment, features of apoptotic cell death were also significantly (p < 0.001) more prevalent in nuclei of TH+ neurons in cultures prepared from WT versus NL mouse pups.These results suggest that caspase 2 may play a role in modulating the MPTP-induced damage to the nigrostriatal dopaminergic system.

Research highlights
► Homozygous caspase 2 null mice are less sensitive to MPTP toxicity.
► Mesencephalic cultures of caspase 2 null mice better survive MPP+.
► The knockout of both copies of the caspase 2 gene is required for protection.